Abstract The prevalence of obesity remains high in American children aged 2-5 while one in three Head Start children is overweight or obese. The proposed study is designed to test the efficacy of an early childhood obesity prevention program, ?Obesity Prevention in Head Start: The Mranos! Program?, which promotes healthy growth in predominantly Latino children in Head Start. The Mranos! includes center-based (policy changes, staff development, gross motor program, and nutrition education) and home-based (parent engagement/ education and home visits) interventions to address key enablers and barriers in obesity prevention in young children. In partnership with Head Start, we have demonstrated the feasibility and acceptability of the proposed interventions to influence energy-balance-related behaviors favorably in Head Start children. Using a three-arm cluster randomized design, 21 Head Start centers in equal number will be randomly assigned to one of three conditions: 1) a combined center- and home-based intervention, 2) center-based intervention only, or 3) control. The interventions will be delivered during the academic year (an 8-month period). A total of 525 3-year-old children (52% females; n=25 per center at baseline) will be enrolled in the study and followed prospectively one year post intervention. Data collection will be conducted at baseline, immediate post-intervention, and 1-year follow-up and include height, weight, physical activity (PA) and sedentary behaviors by accelerometry, parent-reports of sleep duration and TV watching time, gross motor development, dietary intakes and food and activity preferences. Information on family background, parental weight, PA- and nutrition-related practices and behaviors, PA and nutrition policy and environment at center and home, intervention program costs, and treatment fidelity will also be collected. The study has three specific aims: 1) to test the efficacy of the Mranos! intervention on healthy weight growth (primary outcome) in normal weight, overweight and obese children, 2) to test the impact of the Mranos! intervention on children's PA, sedentary behavior, sleep, and dietary behaviors (secondary outcomes), and 3) to evaluate cost- effectiveness of the Mranos! intervention. With endorsement of a large local Head Start administrator and a multi-disciplinary research team, the Mranos!, a culturally tailored obesity prevention program, is poised to provide evidence of a policy and environmental approach to prevent early onset of obesity and its cost-effectiveness in low-income Latino preschool children. By targeting multiple behaviors at different levels of influence and in multiple settings, the Mranos! holds great promise of developing long-term health habits that reduce the energy imbalance gap by targeting multiple energy-balance-related behaviors. The Mranos! can be disseminated to various organized child care settings since it is built on Head Start program and its infrastructure?a gold standard in early childhood education, as well as current PA and nutrition recommendations for preschool children.